Arylative Cyclization Research Articles

Ferrocene Catalyzed Radical Cascade Cyclization of Aryl 1,6-Diynes: Access to Cyanoalkylsulfonyl Fluorenes.

A ferrocene-catalyzed cyanoalkylsulfonylative radical cascade cyclization of aryl 1,6-diynes using cycloketone oxime esters and DABCO.(SO₂)₂ (DABSO) is reported. The reaction proceeds with notable chemo- and regioselectivity, without requiring additional oxidants or reductants. Interestingly, the methodology facilitates the formation of an unprecedented dicyanoalkylsulfonylated derivative in the case of electronically deficient aryl 1,6-diynes. Additionally, this transformation is compatible with substrates derived from drugs and bioactive molecules, highlighting its synthetic utility.

Iodine(III)-Catalyzed Oxidative Cyclization of Aryl Amines to Construct N-Alkylbenzimidazoles.

An I(III)-catalyzed oxidative cyclization reaction using selectfluor as the oxidant was developed that converts ortho-substituted anilines to benzimidazoles. The mild reaction requires as little as 0.5 mol % of iodobenzene, and its scope is broad: electron-withdrawing or electron-releasing groups on the aniline portion are tolerated, and cyclic or acyclic N-alkylamines are permitted as ortho-substituents. Preliminary mechanistic investigations suggest that benzimidazole formation occurs via cationic reactive intermediates, and an intramolecular kinetic isotope effect of 1.98 ± 0.05 was measured.

Nickel-catalyzed electrophiles-controlled enantioselective reductive arylative cyclization and enantiospecific reductive alkylative cyclization of 1,6-enynes.

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to the use of aryl or alkenyl metal reagents, and stereoselective or stereospecific alkylative cyclization of 1,6-enynes remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative cyclization of 1,6-enynes with aryl iodides, providing enantioenriched six-membered carbo- and heterocycles in good yields with excellent enantioselectivities. Additionally, we have realized Ni-catalyzed enantiospecific reductive cis-alkylative cyclization of 1,6-enynes with alkyl bromides, furnishing chiral five-membered heterocycles with high regioselectivity and stereochemical fidelity. Mechanistic studies reveal that the arylative cyclization of 1,6-enynes is initiated by the oxidative addition of Ni(0) to aryl halides and the alkylative cyclization is triggered by the oxidative addition of Ni(0) to allylic acetates. The utility of this strategy is further demonstrated in the enantioselective synthesis of the antiepileptic drug Brivaracetam.

Nickel-catalyzed arylative cyclization of 1,6-enynes: arylation of unactivated alkene moieties

We developed catalytic cyclization of 1,6-enynes, whereby an aryl group is introduced at an unactivated alkene moiety.

Hydroxamic Acids as PARP‐1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

AbstractPoly(ADP‐ribose)polymerase‐1 (PARP‐1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N−O substituted phenanthridinones form a complex interplay with PARP‐1. A series of cyclic aryl hydroxamic acids, N‐(benzyloxy)‐ and N‐(hydroxy)phenanthridinones, were prepared through a ligand‐free methodology from N‐(benzyloxy)benzamides using dual C−H/N−H bond activation. Three of the computed hit compounds exhibited significant activity in cell‐based and enzymatic assays, inhibiting PARP‐1 in the low‐nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA‐MD‐231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N‐(benzyloxy)‐ and an N‐(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target‐specific design to minimize toxicity and side effects.

DFT mechanistic insights into the Ni(II)-catalyzed enantioselective arylative cyclization of tethered allene-ketones.

Density functional theory (DFT) has provided a detailed mechanistic picture for the redox neutral nickel(II)-catalyzed arylative cyclization reactions of a tethered allene-ketone with arylboronic acids. A mechanistic rationale for the high diastereo- and enantioselectivity achieved experimentally at high reaction temperature was uncovered through modeling the reaction with a chiral ligand and the predicted stereochemical outcome corroborates with experimental results. An unprecedented pathway for the base-free organoboron transmetalation pathway was revealed and the regioselectivity of migratory insertion of tethered allene-ketones as well as the stability of the possible allylnickel isomers (σ-allyl vsp-allyl) were clarified. The multifaceted nature of the reaction is revealed with certain elementary steps preferring cationic compared to the neutral state.

Photocatalytic Cascade Cyclization of Aryl Haloalkynyl Ketones Forming Cyclopenta[b]naphthalene Derivatives

An efficient metal-free, photoredox-mediated cascade cyclization of aryl 1-haloalk-5-ynyl ketones has been developed. Using catalytic amounts of eosin Y (EY) and EtNMe2 as a reductive quencher, various aryl 1-haloalk-5-ynyl ketones have been transformed into the corresponding cyclization products in up to 98% yield. As a result, synthetic access to differently α-functionalized cyclopenta[b]naphthones and direct construction of cyclopenta[b]naphtholes has been developed.

CuBr2@g-C3N4-catalyzed cyclization of aromatic alkyne ketones to obtain indenones with K2S2O8 under blue light irradiation

We developed a new scheme of preparing indenones by cyclization of aromatic alkyne ketones based on an admixture of photocatalysts CuBr2@g-C3N4. Also, benzoylindenone was obtained in the yield of 95.2% under blue light at room temperature. By screening the experimental conditions, the mechanism of CuBr2@g-C3N4 catalyzed aryl cyclization was the formation of cyclic 1H-inden-1-one compounds by the generation of transfer electrons excited under blue light. According to the goal of sustainable development of green chemistry, an economical method for preparing indenone from aromatic alkyne ketone was proposed by our team.

Recent Progress in Arylmetalative Cyclization/Annulation of Functionalized Alkynes with Organoboranes

AbstractAchieving complex molecular assemblies in modular modes is always one of the top priorities of the organic chemist. Cyclization/annulation of functionalized alkynes through carbo metalation has an impactful swath in synthetic organic chemistry. There have recently been considerable contributions in this arena uncovering several new chemical spaces towards new solutions for various fields of biology. On the other hand, organoboronic reagents are fascinating reactive chemprobs, are partake in a broad range of chemical transformations. Particularly utility of these reagents in the carbo‐metalation of alkynes is the subject of high perusal in organic chemistry. To this degree, tuning various transition‐metal catalysts with organoboranes and functionalized alkynes is an intriguing subject for the synthesis of various classes of acyclic and cyclic adducts. Mechanistically, these arylative cyclizations proceed through initial aryl‐metalation on alkynes which provides alkenyl metal species, that concomitantly react with the pendent electrophile. The stereo‐ and regioselective reactivity of this C‐metal is steered by chelation with the coordinating group and/or electrophile on alkyne. In this review, we focused on the critical achievements of the field with the emphasis on the stereoselective capture of the vinyl metal complex with a pendent electrophile. In this field, compilation of the detailed mechanistic pathways in this realm would be helpful to find the gaps and hence to discover novel transformations.

De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization

We report an efficient method to prepare polysubstituted 3-hydroxypyridines from amino acids, propargyl alcohols, and arylboronic acids. The process involves Pd(0)-catalyzed anti-selective arylative cyclizations of N-propargyl-N-tosyl-aminoaldehydes with arylboronic acids (“anti-Wacker”-type cyclization), oxidation of the resulting 5-substituted-3-hydroxy-1,2,3,6-tetrahydropyridines to 3-oxo derivatives, and elimination of p-toluenesulfinic acid. This method provides diverse polysubstituted 3-hydroxypyridines, whose hydroxy group can be further substituted by a cross-coupling reaction via a triflate.

Palladium(0)‐Catalyzed Anti‐Selective Addition‐Cyclizations of Alkynyl Electrophiles

Invited for the cover of this issue is the group of Hirokazu Tsukamoto at Tohoku University (current affiliation: Yokohama University of Pharmacy). The image depicts anti-selective arylative cyclization reactions of alkynyl aldehydes with arylboronic acids under palladium catalysis in methanol to afford endo- and exo-cyclic products. Read the full text of the article at 10.1002/chem.202203068.

Construction of a Pentacyclic Framework Enabled by Nickel Catalysis.

We present a novel nickel-catalyzed reaction of indole-tethered 2-alkynylphenol esters with various (hetero)aryl boronic acids, resulting in the synthesis of diversely functionalized pentacyclic benzofurocyclohepta[b]indole derivatives. This unprecedented cascade reaction involves the arylative cyclization of alkynes, nucleophilic attack of the indole moiety on the oxonium ion intermediate, 1,2-alkyl group migration, and aromatization. The synthesized molecules exhibit exceptional cytotoxicity against multiple cancer cell lines while maintaining biocompatibility toward healthy cells.

Rh(III)-catalyzed [4 + 1] cyclization of aryl substituted pyrazoles with cyclopropanols via C-H activation.

A rhodium-catalyzed formal [4 + 1]-cyclization reaction of aryl substituted pyrazoles with cyclopropanols via C-H bond activation/cyclization processes to selectively construct a series of carbonyl functionalized pyrazolo[5,1-a]isoindoles is described. The reaction features good functional group compatibility and a broad substrate scope with respect to both cyclization components with up to 84% yields. Mechanistic studies indicated that the C-H cleavage might be the rate-determining step in this transformation.

Mechanistic insight for tunable regioselective cyclization of aryl propiolates with radicals:ipso-versus ortho-cyclization

A computational study of the reaction mechanism of aryl propiolates with various radicals is carried out employing DFT and coupled-cluster methods, such as coupled-cluster singles and doubles with perturbative triples [CCSD(T)].

Frontispiece: Nickel‐Catalyzed Arylative Cyclizations of Alkyne‐ and Allene‐Tethered Electrophiles using Arylboron Reagents

This review summarizes recent progress in nickel-catalyzed arylative cyclizations of alkyne- and allene-tethered electrophiles using arylboron reagents, which are useful methods for the preparation of diverse carbo- and heterocyclic products. In many cases, nickel catalysis enables unique modes of reactivity not readily available to other metal catalysts. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described. More information can be found in the review article by S. M. Gillbard and H. W. Lam et al. (DOI: 10.1002/chem.202104230)

Highly exo selective, photochemically promoted cyclization of iodoallene derivatives

AbstractA photochemically promoted intramolecular cyclization of aryl‐, vinyl‐, and alkyliodo allenes has been developed. The optimal conditions employed [Ir(ppy)2(dtbbpy)]PF6 (1 mol%) as catalyst affording products with high exo selectivity in moderate to good yields. Chiral substrates showed diastereoselectivity of up to 95/5 favoring trans product.

Nickel-Catalyzed Arylative Cyclizations of Alkyne- and Allene-Tethered Electrophiles using Arylboron Reagents.

The use of arylboron reagents in metal‐catalyzed domino addition–cyclization reactions is a well‐established strategy for the preparation of diverse, highly functionalized carbo‐ and heterocyclic products. Although rhodium‐ and palladium‐based catalysts have been commonly used for these reactions, more recent work has demonstrated nickel catalysis is also highly effective, in many cases offering unique reactivity and access to products that might otherwise not be readily available. This review gives an overview of nickel‐catalyzed arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described.

Cu-mediated vs. Cu-free selective borylation of aryl alkyl sulfones.

A Cu-catalysed borylation of aryl alkyl sulfones was developed for the high yield synthesis of versatile arylboronic esters using a readily prepared NHC-Cu catalyst. In addition, the selective cleavage of either alkyl(C)-sulfonyl or aryl(C)-sulfonyl bonds of a cyclic sulfone via Cu-free or Cu-mediated processes generates the corresponding sulfinate salts, which can be further derivatised to provide sulfonyl-containing boronate esters, such as sulfones and sulfonyl fluorides.

Access to Indole-Fused Benzannulated Medium-Sized Rings through a Gold(I)-Catalyzed Cascade Cyclization of Azido-Alkynes.

Because benzannulated and indole-fused medium-sized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indole-fused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollow-shaped C-dtbm ligand for the construction of a nine-membered ring.

Nickel-catalyzed asymmetric arylative cyclization of N-alkynones: Efficient access to 1,2,3,6-tetrahydropyridines with a tertiary alcohol

Nickel/(S)-t-Bu-PHOX complex catalyzed asymmetric arylative cyclization of N-alkynones has been achieved, delivering 1,2,3,6-tetrahydropyridines containing a chiral tertiary alcohol in high yields and excellent enantioselectivities, which provides efficient access to chiral tetrahydropyridine and piperidine analogues.